Doxycycline, also designated by α-6-deoxy-5-hydroxytetracycline or by α-6-deoxyoxytetracycline, is a semi-synthetic broad spectrum antibiotic of molecular structure (I) disclosed for the first time in the U.S. Pat. No. 3,019,260.

The U.S. Pat. No. 3,019,260 discloses the preparation of salts of doxycycline by addition of acids to doxycycline until a pH of less than 4. Salts of the acids hydrochloric, sulfate, phosphate, trichloroacetate, oxalate, citrate, gluconate are referred to be prepared according to the general procedure taught by the authors.
The U.S. Pat. No. 3,200,149 discloses the preparation of 6-epi-doxycycline (II) and in example XXXIX discloses the preparation of salts of 6-epy-6-deoxy-5-oxy-tetracycline such as the hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, glycolic, gluconic, gulonic, succinic, arysulfonic.

The salts are prepared by dissolving 6-epi-6-deoxy-5-oxy-tetracycline in methanol containing an equimolar amount of the acid. The salts are precipitated by addition of ether to the methanolic solution and are isolated by filtration and drying. No analytical data supporting the salts formation is presented neither the yield is reported. The scope of this patent was to disclose 6-epi-6-deoxytetracyclines, D-ring substituted analogs, 11α-substituted analogs and D-ring-11α-substituted analogs as well as the method of producing these compounds. The inventors use the designations “6-epi” and “a” interchangeably to refer to 6-epi-6-deoxy tetracyclines.
The patent GB1228629 discloses the use of doxycycline salts to prepare aqueous solutions with polyvinylpyrrolidone for parenteral, oral and topical administration. The salts used were the hydrochloride, hydrobromide, sulfate, nitrate, ascorbate, citrate, gluconate, lactate, isonicotinate, gentisinate, pantothenate, salicylate, glucoronate, formate and glutamate. The inventors argued that these solutions were surprisingly stable and topically well tolerated.
The patent BE896423 discloses alkyl sulfate salts of doxycycline of formula (III) where R is an alkyl radical, saturated or unsaturated, linear or branched chain, with 6 to 18 carbon atoms.

The salts are prepared by treating doxycycline base with a stoichiometric amount of the alkylsulfuric acid or by reacting an inorganic salt of doxycycline with an alkaline or ammonium salt of the alkylsulfuric acid. In both cases the preparation is carried out in water or in aqueous alcohol solutions. According to the inventors, the alkyl sulfate groups decrease the surface tension of doxycycline and increase the liposolubility, the powder dispersion as well as the wettability effect.
The U.S. Pat. No. 3,932,490 discloses doxycycline aceturate (IV) and its preparation by reaction of doxycycline with the aceturic acid (acetylaminoacetic acid).

To prepare the salt the inventors treat a solution of doxycycline with a solution of an equimolar amount of acetylamino acetic acid and isolate the product by evaporation of the solvent or by lyophilization of the reaction mixture. The product is characterized by elemental analysis, melting point, solubility and infrared in Nujol. The invention teaches that doxycycline aceturate is more soluble in water than doxycycline and therefore is more suitable for parenteral administration.
The U.S. Pat. No. 4,877,559 discloses the preparation of doxycycline p-toluenesulfonate, compound of formula (Y), by addition of p-toluenesulfonic acid to the solution of doxycycline obtained by hydrogenation of methacycline, in a solvent which is a non-solvent for the salt, for example, methanol.

The product obtained was characterized by circular paper chromatography.
Minocycline, compound of formula (VI), also designated by 7-dimethylamino-6-demethyl-6-deoxytetracycline, is a semi-synthetic broad spectrum antibiotic of molecular structure (I) disclosed in the U.S. Pat. No. 3,226,436.

This patent refers to the prophetic preparation of the hydrochloride, sulfuric and trichloroacetic salts of minocycline.
The patent application US20090099376 refers to the use of minocycline salts of acetic, benzoic, maleic and succinic acids, among others, in the preparation of tigecycline, but it does not disclose minocycline oxalate salt. No description on the preparation of the above salts is provided neither analytical data showing the characterization of the mentioned salts is presented.
Tetracycline, compound of formula VII, formerly designated by omegamycin, is an antibiotic produced by fermentation.

The U.S. Pat. No. 2,886,595 refers to the preparation of salts of tetracycline such as the citrate, the tartaric, the benzoate, the acetate, the succinate, among others but not to the oxalate salt. General procedures are referred to prepare the salts such as the pH adjustment of a solution of tetracycline to a point just below that at which the antibiotic begin to separate, adding stoichiometric amounts of acid to a solution of tetracycline base in water or organic solvent, to form the acid addition salt. The solid salt is isolated by evaporation of the salt solution, or by lyophilization, or by collecting the precipitated salt by filtration, or by precipitating the salt by addition of another organic solvent. The examples given describe the extraction of tetracycline from fermentation broth and described only the preparation of tetracycline hydrochloride and tetracycline formate. These salts are characterized only by melting point.
Demeclocycline (VIII), also known as 7-chloro-6-demethyltetracycline, an antibiotic manufactured by fermentation was disclosed in the U.S. Pat. No. 2,878,289.

The U.S. Pat. No. 2,878,289 refers that demeclocycline form salts of the same type and in general manner as do the tetracyclines and that the acid salts can be formed by treatment of demeclocycline with acids of pH less than about 4. The authors refer to the acetate salt and other organic salts but did not specify further organic salts besides acetate neither give examples on how to prepare them. No examples, neither detailed descriptions are given on the preparation of organic salts of demeclocycline.
Sancycline, also designated by 6-Demethyl-6-deoxy-tetracycline (IX), a semi-synthetic antibiotic was disclosed in the U.S. Pat. No. 3,019,260.

The U.S. Pat. No. 3,019,260 refers to the preparation of acid salts such as trichloroacetate, citrate, oxalate, among others but does not refer to the maleate salt. The inventors refer that the mineral acid salts of the tetracyclines therein disclosed can be prepared by treatment with acids such as hydrochloric acid at pH less than about 4 and that the acid salts such as the sulfate, phosphate, trichloroacetate, oxalate, citrate and gluconate may be formed in a similar manner. The examples teach how to obtain the hydrochloride salt but do not teach how to prepare the organic acid salts neither a description on the preparation of these salts is provided.
The patent GB901209 discloses polyvalent metal salts complexes of sancycline and refer in example V to the preparation of acid addition salts of sancycline by adding mineral acids to methanolic solution of sancycline. The salts are isolated by evaporation of the aqueous solution or by addition of a non-solvent. The hydrochloride, the hydrobromide, the sulfate, the nitrate, the subsalicylate, the phosphate and the tannate (in example VII) salts are prepared according to the example. No disclosure is made with respect to the maleate acid addition salt.
Lymecycline, compound of formula X, also designated by N-lysinomethyltetracycline, is a semi-synthetic antibiotic derived from tetracycline.

The U.S. Pat. No. 3,042,716 refers that acid addition salts of lymecycline can be formed, namely, the hydrobromic, the phosphoric, the sulfuric, the acetic, the tartaric, the malic, the citric and the gluconic acids but do not refer to the benzoic, succinic, maleic and oxalic acid addition salts. No description on the preparation of these salts is presented and the examples do not teach how to prepare these salts.
In general, the prior art gives insufficient or no detail on the preparation of the organic salts of tetracyclines. Most of the patents disclose the preparation of the salts by stating that they can be prepared by mixing the tetracycline with the organic acid in equimolar proportions or by mixing the tetracycline hydrochloride derivative with a metal salt of the organic acid. When examples are given, the description of the methods is insufficient and no reference is made to technical problems that may be encountered during the preparation of the salts. Moreover, the analytical data presented is insufficient to demonstrate the identity and the purity of the salts. For example, analytical methods showing the formation of the acid addition salt by protonation of the amine groups of the tetracyclines such as H1-NMR, or the presence of the carboxylate anion in the salt, such as the infrared spectra of the product, are not presented. Additionally, the description of salts in the prior art does not provide sufficient analytical data about the purity of the organic acid addition salts obtained. In the course of the work carried out in this invention, technical problems were encountered in the preparation of the organic acid salts of tetracyclines and, contrary to the prior art disclosures, it was observed that, under the conditions described, the products isolated are not the desired salts but the base tetracycline compounds, or, mixtures of the tetracyclines with the organic acids.
Adverse effects of acidic doxycycline inorganic salts are described in the prior art. For example, gastric ulcers induced by doxycycline hydrochloride, a salt with a pH of about 3, have been associated with the caustic effect on the esophageal and gastric mucosa of this very acidic salt. Doxycycline is believed to act through a direct caustic effect on the esophageal and gastric mucosa, likely due to its acidic nature (Reference can be made, for example, to: Gastroenterology Research, 2012, Vol. 5, Nr. 6, December 2012, pages 236-238, Aviva Leber, Jeff Stal, Sherman A, Bini E J. Pill-induced gastric injury. Am J Gastroenterol, 1999; 94(2):511-513, Carlborg B, Densert O, Lindqvist C.; Laryngoscope, Tetracycline induced esophageal ulcers, a clinical and experimental study 1983; 93(2): 184-187). In animal studies, direct exposure of esophageal mucosa to tetracycline causes deep ulcerations (see, for example: Carlborg B, Densert O, Lindqvist C., Tetracycline induced esophageal ulcers, a clinical and experimental study, Laryngoscope. 1983; 93(2): 184-187). Furthermore the pill formulation is an important contributing factor, with a higher risk of esophageal ulcerations associated with capsules due to their gelatinous shell and tendency to stick and lodge in the esophageal mucosa (see, for example: Corleto Y D, DAlonzo L, Zykaj E, Carnuccio A, Chiesara F, Pagnini C, Di Somma S, et al, A case of oesophageal ulcer developed after taking homeopathic pill in a young woman, World J Gastroenterol. 2007; 13(14):2132-2134].